ENHANCEMENT OF MELPHALAN ACTIVITY BY INHIBITION OF DNA POLYMERASE-ALPHA AND DNA POLYMERASE-BETA

Our previous studies exploring melphalan resistance in the human rhabd omyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-a lpha and DNA polymerase-beta. The present study evaluated the alterati on of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DN A polymerase-beta was inhibited using dideoxycytidine (DDC). Administr ation of AG or DDC did not produce toxicity or demonstrate antineoplas tic activity when given alone. AG (90 mg/m(2)) enhanced the activity o f melphalan against TE-671, with growth delays increasing by 8.4, 15.8 , and 21.2 days over the regimen with melphalan only. AG (180 mg/m(2)) only modestly increased melphalan activity against TE-671 MR, with th e growth delays increasing from 9.6 and 12.1 days using melphalan alon e to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m(2)) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produc ed no additional toxicity. DDC modestly enhanced the activity of melph alan plus AG against TE-671 MR. AG plus O-6-benzylguanine did not incr ease the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-6 71 or TE-671 MR, AG (90 mg/m(2) and 180 mg/m(2)) inhibited DNA polymer ase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-67 1 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% i n TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnose d, melphalan-sensitive tumors.